New immunotherapy to fight bacteria


An estimated 23,000 people in the U.S. die each year of antibiotic resistant bacterial infections, according to the Centers for Disease Control and Prevention (CDC). A UK government-commissioned review reports that such infections take 700,000 lives per year globally.

Image: Illustration of a bacteria; Copyright: Lehigh University

This illustration shows how bacterial surfaces can be remodeled to recruit antibodies using unnatural D-amino acids to install a reactive chemical 'handle'; © Lehigh University

If no action is taken, experts say that by 2050 the number of people to die of bacterial infections worldwide will increase by an additional 10 million per year - more than currently die from cancer. These startling figures demonstrate why the discovery of alternatives approaches to fighting bacteria is a national and worldwide research priority.

Marcos Pires, assistant professor of chemistry at Lehigh University, is pioneering one promising route: instead of a treatment that attacks the bacteria directly, he is working on a method that would allow the immune system do the dirty work. This novel technique takes a page out of the cancer treatment playbook, as immunotherapy is widely seen as among the most promising of emerging anti-cancer strategies.

Pires' research has attracted the attention of the American Chemical Society which recently recognized him with its inaugural ACS Infectious Diseases Young Investigator's Award acknowledging "outstanding early career researchers" based on the significant contributions they have made to the infectious disease field. The recipients will be honored at a symposium on Tuesday, August 23rd in Philadelphia held in conjunction with the ACS Fall National Meeting.

Pires first revealed his innovative method of molecularly tagging pathogenic bacteria to attract antibodies in an article in ACS Chemical Biology in 2014. In it, Pires and his team demonstrate the initial steps toward a novel, synthetic immunological approach for remodeling the surface of Gram positive bacteria by exploiting its inherent "promiscuity"- its tendency to incorporate extracellular D-amino acids into its peptidoglycan, the mesh-like scaffold that comprises much of the bacterial cell wall.

"Our method hijacks the peptidoglycan biosynthetic machinery to install a reactive chemical 'handle' that gets incorporated into the cell wall yielding a cell surface that recruits antibodies," says Pires. "Essentially, this tags the bacterial cell surface with a bull's eye marking it for destruction by the immune system."

Pires and his team are now fine-tuning their strategy. In a recent ACS Infectious Diseases cover story, they revealed a two-step dipeptide peptidoglycan remodeling strategy aimed at introducing haptens (small molecules that, when combined with a larger carrier such as a protein, can elicit the production of antibodies that bind specifically to it) at an alternative site within the stem peptide to improve retention and produce higher levels of antibody recruitment to bacteria cell surfaces.

"We believe that based on our strategy, it should be possible to use synthetic dipeptides displaying chemical 'handles' to label bacteria cell surfaces for imaging and therapeutic applications," says Pires. "More importantly, we propose that our method could provide the basis for improved immunomodulation strategies to combat bacterial infections."

The team will next use its unique strategy to attack the "Big Bad" of bacterial infections - the Gram negatives.

They are also exploring whether this strategy can work in live animal infection models and, for diagnostic purposes, whether they can quickly identify bacteria based on their labeling with synthetic D-amino acids.; Source: Lehigh University

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